winter 2013 d˙ a˛ˇ ˇ - dermatology in practice · 2019. 5. 22. · the careful shopper must be...
TRANSCRIPT
Comment
3 The changing work of the dermatologist
Neill Hepburn
Investigation
4 Common skin allergens: hazards on the high street
Laura Cuddy and Ian Coulson
Review
9 The genetics of basal cell carcinoma
Nicholas J Collier, Faisal R Ali
and John T Lear
Therapeutics
14 Update on the treatment of actinic keratosis
Colin Morton, Megan Mowbray,
Colin Clark, Girish Gupta,
Robert Herd and Colin Fleming
FAQs19 What is ‘Breslow
thickness’ in melanoma?
Richard Jerrom and Neill Hepburn
Dermatologyin practice
Winter 2013 Volume 19 Number 4 www.dermatologyinpractice.co.uk
Other features8 PCDS
12 Reader survey results
18 Monk’s moments
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Doublebase™ Gel Isopropyl myristate 15% w/w, liquid paraffin 15% w/w. Uses: Highlymoisturising and protective hydrating gel for dry skin conditions. Directions: Adults, childrenand the elderly: Apply direct to dry skin as required. Doublebase Dayleve™ Gel Isopropylmyristate 15% w/w, liquid paraffin 15% w/w. Uses: Long lasting, highly moisturising andprotective hydrating gel for dry skin conditions. Directions: Adults, children and the elderly:Apply direct to dry skin morning and night, or as often as necessary.Contra-indications, warnings, side effects etc: Please refer to SPC for full details beforeprescribing. Do not use if sensitive to any of the ingredients. In the unlikely event of a reactionstop treatment. Package quantities, NHS prices and MA numbers:Doublebase Gel: 100g tube £2.65, 500g pump dispenser £5.83, PL00173/0183.Doublebase Dayleve Gel: 100g tube £2.65, 500g pump dispenser £6.29, PL00173/0199.
Legal category: P MA holder: Dermal Laboratories, Tatmore Place, Gosmore, Hitchin, Herts,SG4 7QR. Date of preparation: November 2012. ‘Doublebase’ and ‘Dayleve’ are trademarks.
Rx by name for formulation of choice
Doublebase DayleveTM GelDoublebaseTMGelIsopropyl myristate 15% w/w, liquid paraffin 15% w/w
Original emollient Gel
• Emolliency like an ointment• Cosmetic acceptability like a cream
Adverse events should be reported. Reporting forms and information can befound at www.mhra.gov.uk/yellowcard. Adverse events should also bereported to Dermal.
Enhanced emollient Gel
• Highly emollient long lasting protection• As little as twice daily application
No other emollients perform quite like them!Doublebase – The difference is in the GELS
www.dermal.co.uk
High
oil content
+ glycerolHigh
oil & glycerol
content +
povidone
HyBR
ID IM
AGES
/CUL
TURA
/SCIE
NCE P
HOTO
LIBR
ARy
ensuring patients followed pathways involvingexcision, or re-excision for melanoma; werecounselled appropriately; and then underwentappropriate follow-up. We now consider awhole variety of therapeutic agents and havereal engagement with oncologists, and evenradiologists, as the discussions have becomemore complex. Similarly, Colin Morton et aldescribe new treatment options for actinickeratoses. I am aware that I now use much lessliquid nitrogen in the clinic and spend muchmore time explaining to patients how to usethe new topical agents. The actinic keratosisinformation sheet I use has increased from asingle page to two pages in length. In myregular visits out to primary care teams I amalways asked about actinic keratoses! All thisseemed quite remote five years ago.
There are always new opportunities comingalong. While health and safety legislation andawareness have dramatically reduced thenumber of patients we see with industrialcontact dermatitis, the rise in reactions to self-care products keeps the patch-test clinicsgoing. Laura Cuddy and Ian Coulson describesome of the hazards patients encounter on thehigh street. Detecting the culprit in the patch-test clinic can often be challenging, but it’sgood to have to do a little detective work, if only to keep the brain working. Perhaps that is why dermatology is such fun –it offers a fantastic balance of doingand thinking.
Neill Hepburn, Editor
3
At school I really enjoyed woodwork,such that I hoped to become a
joiner – an ambition thwarted by my mother,who had other ideas! I have always enjoyeddoing things with my hands and, indeed,built a kit car a few years ago. It’s notsurprising, therefore, that skin surgery hasalways been an enjoyable part of my work. Ilike the visual aspects of working out how toremove the tumour and, more challengingly,how to reconstruct the defect. I like the ‘feel’of the tissues and get satisfaction in seeingthe results. Barry Monk’s article on thechanging nature of the work we do asdermatologists is poignant. Many of the boysI shared a bench with at school went on tothe highly regarded craft apprenticeships,working as tool makers and so on. I wonderwhat has happened to them. As the economywas ‘rebalanced’ in the 1980s, much of themanufacturing industry moved abroad andthose trades were lost. Dermatology isstarting to go through a similar transition.Although teledermatology seemed to be thethreat a decade ago, it is now becoming moremainstream and, in limited situations, ratheruseful. What is more surprising is how thephysical treatments are changing.
In this issue, Nicholas Collier, Faisal Ali andJohn Lear outline the new genetics of basal cellcarcinoma, which are leading to newtreatment possibilities. My days spent cuttingout basal cell carcinomas may be approachingtheir end. Our skin cancer multidisciplinaryteam meetings have changed from simply
�
�
Published by
a division of Hayward Group LtdThe Pines, Fordham Road, Newmarket CB8 7LG, UK. Tel +44 (0)1638 723560.Fax +44 (0)1638 723561. email [email protected]
Publisher Mary Read.Editorial Director Robin Jones.Senior Sub Editor Anne-Claire Bouzanne.Sub Editor Josie Mitchell.Art Editor Richard Seymour. Publications Manager Andrea Bucceri.
The data, opinions and statements appearing in the articles herein are those of the contributor(s) concerned; they are not necessarily endorsed by the sponsors,publisher, Editor or Editorial Board. Accordingly,the sponsors, publisher, Editor and EditorialBoard and their respective employees, officers and agents accept no liability for theconsequences of any such inaccurate ormisleading data, opinion or statement.
Design & Editorial OfficeHayward Medical Communications, 8–10 Dryden Street, Covent Garden, London WC2E 9NA. Tel: +44 (0)207 2404493. Fax: +44 (0)207 2404479. email: [email protected]
The title Dermatology in practice is the property of Hayward Group Ltd and, together with the content, is bound by copyright. © 2013 Hayward Group Ltd. All rights reserved.
ISSN 0262-5504 (Print). ISSN 2049-8446 (Online).
Printed by Williams Press Ltd.
Cover picturePETER DAzELEy/GETTy IMAGES
Editor
Neill Hepburn MD FRCP
Consultant Dermatologist, Lincoln County Hospital.
Editorial Board
W Iain F Henderson MB ChB DRCOG DPD
GP Principal, Glasgow; Hospital Practitioner, Glasgow Western Infirmary.
Danny Kemmett MB ChB FRCP(Edin)
Consultant Dermatologist, Royal Infirmary of Edinburgh.
Barry E Monk MA FRCP
Consultant Dermatologist, BMI The Manor Hospital, Bedford
Tom Poyner FRCP(Lond) FRCP(Glasg) FRCGP DPD
ormer GP, Stockton-on-Tees; HonoraryLecturer, University of Durham.
Jane Watts RGN ENB 393 998
Senior Dermatology Nurse, Whipps Cross University Hospital, London.
Irshad Zaki BMed Sci(Hons) BM BS MRCP
Consultant Dermatologist, Solihull Hospital.
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Comment
HaywardMedical Communications
www.dermatologyinpractice.co.uk
The changing workof the dermatologist
� Dermatologists now have real engagement with
oncologists and radiologists,as team discussions have
become more complex
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
The high street has taken a pounding since the
start of the recession, but the hair and beauty
sector has flourished and is estimated to be
worth billions of pounds. Many people feel
that they are not blessed with natural beauty
and need a little helping hand. This may be
simply purchasing moisturisers or cosmetics
over the counter or visiting the hairdresser or
beauty salon. However, they may not fully ap-
preciate the risks that they are exposing their
skin to. The British Association of Dermatolo-
gists estimates that contact dermatitis accounts
for between 4 and 7% of dermatological con-
sultations and about 1–3% of the population
are allergic to ingredients in cosmetics.1 Even
when a contact allergy has been identified,
shoppers need eagle-like vision to interrogate
the ingredients’ lists of cosmetics, or be persist-
ent and peel back one layer of label to reveal the
list lurking below! The list of allergens com-
monly used in high-street products or services
is surprisingly large, and the consequences
wide-ranging.
Methylchoroisothiazolinone and methylisothiazolinone
Methylchoroisothiazolinone (MCI) and methyl-
isothiazolinone (MI) have recently attracted grow-
ing media interest. They are common biocides in
household products such as detergents and clean-
ers, as well as in personal care items like shampoos,
moisturisers, shower gels and wet wipes. They
were first used in the 1970s and, during the 1980s,
there was an ‘epidemic’ of MCI- and MI-related
contact dermatitis in Europe. As a result, the con-
centrations of these drugs in personal care items
were restricted.2 Since the early 2000s, MCI has
been used in isolation in popular body care prod-
ucts. In 2004, a report by the European Scientific
Committee on Cosmetic Products and Non-Food
Products intended for Consumers concluded that
‘the proposed use of Methylisothiazolinone as a
preservative at a maximum concentration of
0.01% (100 ppm [parts per million]) in the fin-
ished cosmetic product does not pose a risk to the
health of the consumer’.3
However, MCI and MI appear to be responsible
for an increasing number of cases of allergic con-
tact dermatitis. Data gathered between January
2011 and June 2012 revealed that 6.2% of patch-
Laura Cuddy MRCPSpecialist Registrar in DermatologyIan Coulson BSc MBBSFRCP Consultant inDermatology, BurnleyGeneral Hospital
www.dermatologyinpractice.co.uk
Investigation DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4
4
Common skin allergens:hazards on the high street
test patients had a reaction to MCI/MI at any
concentration.2 With rising levels of sensitisation
in the general population, consideration needs
to be given as to whether their widespread use
in everyday products should be restricted or
even banned.
Even when individuals are aware of their sensi-
tisation, identifying the allergens within the
ingredients’ list is not always easy, as in some
unboxed products that list may be obscured by a
peel-back label (see Figure 1). The careful shopper
must be very persistent and inquisitive when on
an allergen hunt!
ParaphenylenediamineHair dyes are another common cause of allergic
contact dermatitis and individuals are frequently
referred to a dermatologist for patch testing, the
presumed culprit being paraphenylenediamine
(PPD). PPD is an organic compound frequently
used in permanent hair dyes, textiles, dark cosmet-
ics and inks. PPD requires oxidisation to become
coloured and it is the partial oxidised state that
may cause sensitisation and an allergic contact der-
matitis. It may cause eyelid or ear dermatitis, but in
more extreme cases there may be extensive ery-
thema and oedema of the scalp and face. Sensitisa-
tion will often have occurred in childhood or
adolescence and be long forgotten by the time grey
hairs make their unwelcome debut. The first appli-
cation of PPD to hide these grey hairs may then
result in a severe allergic reaction. Hairdressers
may also become sensitised and develop hand
eczema due to regular contact.
� Figure 1. On this bottle of sunscreen, the label has to be peeled back to seeingredients, making it difficult for shoppers to identify allergens
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Like Jack, Dermol can also
do two things at once!
The Dermol family of antimicrobial emollients - for patients of all ages whosuffer from dry and itchy skin conditionssuch as atopic eczema/dermatitis.
• Specially formulated to be effective and acceptable on sensitive eczema skin
• Significant antimicrobial activity against MRSA and FRSA (fusidic acid-resistant Staphylococcus aureus)1
• Over 15 million packs used by patients2
A family of antimicrobial emollientsWASH SHOWER LOTION CREAM BATH
Dermol
Dermol® Wash, Dermol® 200 Shower Emollientand Dermol® 500 Lotion Benzalkonium chloride0.1%, chlorhexidine dihydrochloride 0.1%, liquidparaffin 2.5%, isopropyl myristate 2.5%. Dermol® Cream Benzalkonium chloride 0.1%,chlorhexidine dihydrochloride 0.1%, liquid paraffin10%, isopropyl myristate 10%.Uses: Antimicrobial emollients for the management of dry andpruritic skin conditions, especially eczema and dermatitis, and for use as soap substitutes. Directions: Adults, children and theelderly: Apply direct to the skin or use as soap substitutes.
Dermol® 600 Bath Emollient Benzalkoniumchloride 0.5%, liquid paraffin 25%, isopropylmyristate 25%.
Uses: Antimicrobial bath emollient for the management of dry,scaly and/or pruritic skin conditions, especially eczema anddermatitis. Directions: Adults, children and the elderly: Add to a bath of warm water. Soak and pat dry.
Contra-indications, warnings, side-effects etc: Please refer to SPC for full details before prescribing. Do not use if sensitive to any of the ingredients. In the unlikely event of a reaction stoptreatment. Keep away from the eyes. Take care not to slip in the bath or shower. Package quantities, NHS prices and MA numbers: Dermol Wash: 200ml pump dispenser £3.55,PL00173/0407. Dermol 200 Shower Emollient: 200ml showerpack £3.55, PL00173/0156. Dermol 500 Lotion: 500ml pumpdispenser £6.04, PL00173/0051. Dermol Cream: 100g tube £2.86, 500g pump dispenser £6.63, PL00173/0171. Dermol 600 Bath Emollient: 600ml bottle £7.55, PL00173/0155. Legal category: P MA holder: Dermal Laboratories, TatmorePlace, Gosmore, Hitchin, Herts, SG4 7QR. Date of preparation:
February 2012. ‘Dermol’ is a registered trademark.
Adverse events should be reported. Reportingforms and information can be found atwww.mhra.gov.uk/yellowcard. Adverse eventsshould also be reported to Dermal.
References:1. Gallagher J. et al. Poster presented at EADV Congress 2009.2. Dermol Range – Total Unit Sales since launch. Dermal
Laboratories Ltd. Data on file.
Dermol knocks out Staphand soothes itchy eczema
www.dermal.co.uk
It is important to remember that other ingredi-
ents in hair dyes, such as paratoluenediamine
(PTD), p-aminophenol, m-aminophenol and re-
sorcinol, may also lead to sensitisation.4 Patients
should be told that it is essential to do a patch test
before proceeding with dyeing their hair on every
occasion, whether at home or at the hairdresser’s.
An increasing problem is sensitisation to PPD in
temporary or beach tattoos (see Figure 2). Adver-
tised as ‘henna’, these tattoos often contain large
amounts of PPD, minuscule amounts of (or even
no) henna and an organic solvent – the perfect
storm for sensitisation.
Acrylates
Nail salons have been thriving on the high street
in recent years. According to Local Data Company,
a UK retail consultancy, there has been a 16.5% in-
crease in the number of nail salons since 2008.5 Ar-
tificial nails are an increasingly common cosmetic
enhancement. These, along with other nail cos-
metics such as nail lacquer, nail polish remover
and cuticle remover, come with their own poten-
tial problems. Most nail varnish contains toluene
sulfonamide formaldehyde resin (TSFR), which
often causes an allergic eczema distant from the
hands, most notably a streaky eczema on the neck
(see Figure 3), around the mouth and on the eye-
lids. Individuals who are allergic to nickel may
paint varnish on to their favourite earrings or jean
studs and compound their nickel dermatitis with
nail varnish allergy!
Data from Kwok et al collected between 1996
and 2011 looked at occupational disease in beau-
ticians and found that out of 257 cases of allergic
contact dermatitis, acrylates were the most com-
mon source, affecting 64.1% of patients.6 Acrylates
are contained in acrylic glue (usually methyl
methacrylate), which is used to fix both artificial
nails and eyelashes in place. In salons, ‘gel nails’
are popular with clients due to their durability.
The gel is sculptured to produce an attractive
shape before ultraviolet (UV) light is used to poly-
merise the acrylate and set the nail. If a coloured
nail is desired, then a coloured acrylate or a con-
ventional varnish (which may contain TSFR) is ap-
plied. Nail technicians may develop allergic
contact dermatitis on the hand from the filings,
and in more severe cases airborne particles can
lead to dermatitis affecting the face and neck area
as well. Filing dust extraction systems are recom-
mended to minimise allergen exposure. Client
sensitisation is less common but can produce se-
vere finger pulp eczema (see Figure 4) and severe
nail dystrophy. Women regularly having gel back-
fills should be warned that increased exposure to
UV light can lead to photodamage. Removal of
these artificial nails requires them to be soaked in
acetone for 10–15 minutes, which can cause nail
brittleness. In addition, they can also obscure
other dermatological conditions, such as fungal
nail infections or acral malignancies.
Ultraviolet radiation
In the UK, a golden-brown tan is seen as desirable,
especially among young women. A sample of
young women surveyed in Northern Ireland re-
ported that a tan would make them feel more at-
tractive (47%) and healthier (42%).7 Yet the
consequences of ‘the electric beach’ are often ig-
nored. The Sunbeds (Regulation) Act 2010 came
into effect on 8 April 2011 and states that no person
under the age of 18 years may use a sunbed, be of-
fered the use of a sunbed or be present in the re-
stricted zone (that is, the area where a sunbed is
located). Failure to comply with the Act is a criminal
offence and may incur a penalty of up to £20,000.8
However, this has had limited impact on adoles-
cents determined to get a tan. Sixty-nine young
women aged 15–18 years who regularly used
sunbeds were surveyed about the implications of
the aforementioned legislation. While they did ac-
knowledge some risks of sunbed use, they admitted
to trying to circumvent the restrictions.9
Exposure to ultraviolet (UV) radiation from
sunbeds is one of the potential causes of malig-
nant melanoma. As long as sunbed users, particu-
larly young women, do not change their attitudes
6
Investigation DERMATOLGY IN PRACTICE 2013; Vol 19 No 4
www.dermatologyinpractice.co.uk
� Figure 2. A young man has developed allergic contact dermatitis to a ‘henna’ tattoocontaining paraphenylenediamine
� Figure 3. Neck and chest eczemadue to an allergic reaction to both nailvarnish and nickel
� Figure 4. A nail bar client with fingerpulp eczema
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
out by individuals who are not suitably qualified,
leaving patients vulnerable to complications.
These complications range from erythema,
swelling, bruising, infection and incorrect or su-
perficial placement of the filler to skin necrosis,
late-onset allergy and granulomatous reactions.17
The Department of Health in England has made
recommendations to protect clients, including:
new legislation to classify fillers as prescription
only; formal qualifications for anyone who in-
jects hyaluronic acid or botulinum toxin; and a
register of individuals who perform non-surgical
cosmetic procedures.16
Nickel
Even the money handed over to purchase these
various products and services can cause allergic
contact dermatitis. Contact allergy to nickel is es-
timated to affect about 4.5% of the population.1
The UK Royal Mint began circulating new 5p and
10p coins in January 2012. Prior to this, the coins
were a metal alloy known as cupro-nickel, which
contains 75% copper and 25% nickel. The newer
coins are made of nickel-plated steel and were in-
troduced as a money-saving measure. A small
study by Julander et al found that the amount of
nickel deposited on to the skin when handling
these new nickel-plated coins for one hour was
four times higher than with the previous cupro-
nickel coins. The authors suggest that, due to ex-
posure to higher levels of nickel, these new coins
are a public health concern.18
Concerned consumers can purchase a tool to
test objects, such as jewellery or coins, they sus-
pect of containing nickel. The dimethylglyoxime
test is available commercially and can be used on
objects that come into contact with the skin. It in-
volves combining a few drops of 1% dimethylgly-
oxime in alcohol with 10% ammonium chloride
solution. This mixture is then applied to a cotton
wool tip, which is rubbed for 30 seconds against
and habits, then rates of malignant melanoma will
continue to be affected. Since the 1970s, these
have quadrupled and malignant melanoma is
now the fifth most common cancer in the UK.10
Unusually high melanoma rates are reported
among young women in the north-west of Eng-
land, whereas traditionally they have been higher
in the south, where the days are longer and there
are more hours of sunshine. This change has been
attributed to the fact that young women in the
north-west have increased their use of sunbeds
and take more holidays abroad.11
Even more alarming is the fact that most tan-
ning booths in England do not comply with Eu-
ropean standards. Research published earlier this
year found that nine out of 10 sunbeds examined
in England emitted levels of UV radiation that ex-
ceed the maximum permitted.12 Untold damage is
being done to sunbed users’ skin as vanity is put
before health.
Waxing
Whether done at home or in a beauty parlour, wax-
ing is popular as a semi-permanent form of hair re-
moval. But the risks related to having one’s legs
waxed should not be underestimated. Complica-
tions include burns, folliculitis , pseudofolliculitis,
spreading mollusca, cellulitis and contact dermati-
tis. Allergenic ingredients in the wax itself can in-
clude modified-colophonium derivatives.13 There
are even reported cases of granuloma annulare ap-
pearing on lines of trauma (Koebner phenome-
non). Recent trends in the waxing industry include
extensive removal of pubic hair, including partial
pubic (‘Brazilian’) or complete anogenital (‘full
Hollywood’) waxing. This can lead to genital injury
as well as the aforementioned complications. An
unfortunate 20-year-old Australian woman with
poorly controlled type I diabetes developed life-
threatening Streptococcus pyogenes and herpes sim-
plex infection of her external genitalia following a
routine perineal Brazilian bikini waxing session.14
On a more positive note, it has been hypothesised
that the popularisation of this type of extreme hair
removal has resulted in rates of pubic lice falling.15
Dermal fillers
Regulation of the non-surgical cosmetic proce-
dures such as dermal fillers is a hot topic at the
moment, in part due to the Keogh report which
was a government commissioned report includ-
ing a review of cosmetic treatment procedures re-
leased earlier this year.16 Dermal fillers involve
injecting substances such as hyaluronic acid into
the skin to smooth out wrinkles, scars or depres-
sions. This area of cosmetic enhancement is
largely unregulated and procedures can be carried
7
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Investigation
www.dermatologyinpractice.co.uk
� The British Association of Dermatologists estimates that about1 –3% of the population are allergic to ingredients in cosmetics.
� Methylchoroisothiazolinone and methylisothiazolinone arecommon ingredients in household cleaners as well as beautyproducts. They appear to be an increasing cause of allergiccontact dermatitis.
� Paraphenylenediamine, toluene sulfonamide formaldehyderesin and nickel can cause allergic reactions.
� Research published earlier this year found that nine out of 10sunbeds examined in England emitted levels of ultravioletradiation that exceed the maximum permitted.
Key points
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
PCDS
8
Investigation
www.dermatologyinpractice.co.uk
The Primary Care DermatologySociety (PCDS) held its annualScottish meeting over the weekendof the 9–10 November 2013. There was a very full and variedprogramme. Professor Chris Bunker
gave two outstanding lectures: one on ‘HIV and the skin’ and the other on ‘Penile and perianaldermatology’. Professor Bunker gave a very strongtake-home message that we should have a much lowerthreshold to suspect HIV might be implicated in theaetiology of many dermatological conditions. He alsobelieves that we should be doing more HIV testingbecause, if cases can be picked up earlier, it will helpreduce transmission of the virus. He spoke about theimportance of highlighting patients with HIV who aresymptomatic with dermatological diseases, and mightbenefit from initiating early antiviral treatment. Thiswould be preferable to decisions being made basedsolely on laboratory data.
Dr John English delivered a very informative andentertaining lecture on ‘Allergy testing,’ includinginformation about drug allergies. He spoke about abalanced approach when dealing with consultationsfocused on allergy. Other lectures included ‘Facial rashes’,‘Pyoderma gangrenosum’, ‘The role of the dermatologyliaison nurse’ and a host of other useful topics.
Workshops were also held, including: ‘Update oncontact dermatitis’, ‘Toenails and foot infections,’ and ‘Moh’ssurgery’. There were also sessions on minor surgerydelivered by Dr Christy Chou and his colleagues. Dr Chou’ssuperb teaching is definitely not to be missed by thebudding skin surgeon, or the established GP wanting toimprove their surgical technique.
On the Saturday morning, the PCDS piloted a sessionentitled ‘Dermatology tips for GP registrars,’ with the hopeof inspiring GPs about dermatology at an early stage intheir career. If the evaluations from this meeting arepositive, we plan to run such sessions again. So if you havea registrar in your practice who might be interested infuture dermatology educational sessions, please get themto contact the PCDS.
Here is provisional list of some of the PCDS meetingsplanned for early 2014:•Top Tips in Dermatology, 8 February, Leicester•Top Tips in Dermatology, 1 March, Winchester• Spring Meeting, 14–16 March, Kenilworth•Advanced Dermoscopy, 27 March, Manchester• Essential Dermatology, 3 April, Crewe• Essential Dermatology, 1 May, Newcastle• Essential Dermatology, 14 May, Hemel Hempstead• Essential Dermatology, 21 May, Northampton
Please visit the PCDS website (address below) for a list of all the future meetings taking place and formore information �
Tom Poyner, Former GP, Stockton-on-Tees;
Vice Chair of the Executive Committee
and Trustee of the PCDS
� Figure 5.Dimethylglyoximetest on a new fivepence coin
the object being tested. A pink-red colour on
the cotton tip indicates the presence of nickel (see
Figure 5). 19
Conclusion
It is vital that people be informed of the risks in-
curred by their skin when they use products and
services that are available on the high street. If they
present in primary or secondary care with derma-
tological complications, patients must be advised
and treated appropriately. In cases of suspected al-
lergic contact dermatitis, patients should be ad-
vised to avoid the suspected allergen and be
referred for patch testing to confirm suspicions �
Declaration of interestNone declared.
References1. Bourke J, Coulson I, English J. Guidelines for the management of contact der-matitis: an update. Br J Dermatol 2009; 160: 946–954.2. Urwin R, Wilkinson M. Methylchloroisothiazolinone and methylisothiazolinonecontact allergy: a new ‘epidemic’. Contact Dermatitis 2013; 68: 253–255. 3. The Scientific Committee on Cosmetic Products and Non-Food Products in-tended for Consumers, Opinion Concerning Methylisothiazolinine, 2004.http://ec.europa.eu/health/ph_risk/committees/sccp/documents/out270_en.pdf (last accessed 20/07/13).4. Søsted H, Rustemeyer T, Gonçalo M et al. Contact allergy to common ingredi-ents in hair dyes. Contact Dermatitis 2013; 69: 32–39.5. www.bira.co.uk/assets/download/280 (last accessed 03/11/13)6. Kwok C, Money A, Carder M et al. Occupational disease in beauticians reportedto the health and occupation research network from 1996 to 2011. Br J Dermatol2013; 169(Supp 1): 130.7. Boyle R, O’Hagan AH, Donnelly D et al. Trends in reported sun bed use, sun-burn, and sun care knowledge and attitudes in a U.K. region: results of a surveyof the Northern Ireland population. Br J Dermatol 2010; 163: 1269–1275.8. Sunbeds (Regulation) Act 2010. www.gov.uk/government/uploads/system/uploads/attachment_data/file/216374/dh_125983.pdf (last accessed 20/07/13).9. Lake JR, Thomson CS, Twelves CJ, Davies EA. A qualitative investigation of themotivations, experiences and views of female sunbed users under the age of 18in England. J Public Health (Oxf) 2013 [Epub ahead of print].10. Cancer Research UK. www.cancerresearchuk.org/cancer-info/cancerstats/types/skin/ (last accessed 19/07/13).11. Wallingford SC, Alston RD, Birch JM, Green AC. Regional melanoma incidencein England, 1996–2006: reversal of north-south latitude trends among young fe-males. Br J Dermatol 2013 [Epub ahead of print].12. Tierney P, Ferguson J, Ibbotson S et al. Nine out of 10 sunbeds in England emitultraviolet radiation levels that exceed current safety limits. Br J Dermatol 2013;168: 602–608.13. Goossens A, Armingaud P, Avenel-Audran M et al.An epidemic of allergic con-tact dermatitis due to epilating products. Contact dermatitis 2002; 47: 67–7014. Dendle C, Mulvey S, Pyrlis F, Grayson ML, Johnson PDR. Severe complicationsof a “Brazilian” bikini wax. Clin Infect Dis 2007; 45: e29–e31.15. Chen KS, Yesudian PD. ‘Why Pthirus pubis don’t watch Sex and the City’. Br JDermatol 2013; 169(Supp 1): 143.16. Review of the Regulation of Cosmetic Interventions – Final Report (April 2013)www.gov.uk/government/uploads/system/uploads/attachment_data/file/192028/Review_of_the_Regulation_of_Cosmetic_Interventions.pdf (last accessed20/07/13).17. Cohen JL. Understanding, avoiding, and managing dermal filler complica-tions. Dermatol Surg 2008; 34(Suppl 1): S92–S99. 18. Julander A, Midander K, Herting G et al. New UK nickel-plated steel coins con-stitute an increased allergy and eczema risk. Contact Dermatitis 2013; 68: 323–330.19. Liden C. Nickel. In: Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds). TheHandbook of Occupational Dermatology, 1st edn. Berlin: Springer, 2000: 530.
Tel:
01707 226 024email:
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Nicholas J CollierBMBS BMedSci MRCPDermatology MScStudent, Kings CollegeLondonFaisal R Ali BM BChMRCP DermatologySpecialist Registrar,Salford Royal NHSFoundation Trust,ManchesterJohn T Lear MB ChB MDFRCP DermatologyConsultant,Dermatology Centre,University ofManchester
Basal cell carcinoma (BCC) is the most common
human cancer, with a 30% lifetime risk in those
of European descent.1 Incidence is increasing by
3–10% per annum worldwide2 and it is expected
that, soon, the prevalence will equal that of all
other cancers combined.3 While mortality is
rare, BCC causes considerable morbidity and
burden on health services. BCCs are slow-grow-
ing, locally invasive, malignant epidermal tu-
mours which rarely metastasise (<0.1%).4 The
underlying causal mechanism is a genetic aber-
ration, which may be inherited or acquired.
Primary risk factors are ultraviolet (UV) light ex-
posure and genetic predisposition. Other signifi-
cant risk factors include Fitzpatrick skin types I and
II, immunosuppression, advanced age, male sex,
previous BCCs and chronic arsenic exposure.
Research into the molecular genetics of BCCs in
the past two decades has uncovered many of the
pathways fundamental to their pathogenesis,
leading to potential therapeutic targets. Several
targeted agents are currently being trialled; one,
vismodegib, is licensed in the UK for use in ad-
vanced BCC. Studies to date demonstrate efficacy
of these targeted agents, albeit with frequent and
considerable side-effects, and evidence of resist-
ance and recurrence, which currently limit their
use to a select group of patients.5
Pathway inhibitors, though in their infancy,
offer a novel and exciting avenue for the targeted
treatment of BCC.
Link to genetics
Insight into the molecular pathogenesis of BCC
was derived from the study of patients with hered-
itary basal cell naevus syndrome (HBCNS, or Gor-
lin–Goltz syndrome), first described in 1960 by
Gorlin and Goltz.6 HBCNS is an autosomal domi-
nant condition with mutation of the patched ho-
mologue 1 (PTCH1) gene located on chromosome
9q22.3. PTCH1 encodes a 12-span transmem-
brane protein, Patched-1 (Ptch-1), which acts as
the receptor for the hedgehog proteins and func-
tions as a tumour suppressor. HBCNS has variable
expression and incomplete penetrance, and 25%
of cases arise from de novo mutations.7
Clinical features of HBCNS include the develop-
ment of multiple BCCs, with a mean age of onset
of 25 years. Other common features include pal-
moplantar pits, odontogenic cysts, calcification of
the falx cerebri, skeletal abnormalities and the de-
velopment of medulloblastomas.
Hedgehog pathway
Investigations into body segmentation in fruit
flies (Drosophila melanogaster) in the 1980s pro-
duced embryos covered with small pointy projec-
tions resembling a hedgehog.8 This led to the
discovery of the hedgehog pathway. The mam-
malian hedgehog family includes three orthologs:
sonic hedgehog (SHH), which was described first,
Indian hedgehog (IHH) and desert hedgehog
(DHH). The hedgehog pathway is well preserved
throughout many species.
SHH encodes a pro-protein, which undergoes
cleavage and lipidation producing the sonic
hedgehog ligand (Shh). Shh is intrinsic to early
embryonic development, acting as a morphogen
in neural tube formation, and is involved in
musculoskeletal and integumentary system devel-
opment. Germ-line mutations to SHH can cause
severe congenital malformations such as holo-
prosencephaly. In adult tissues, the SHH pathway
is largely quiescent except in hair, skin and
stem cells.
Key components of the SHH pathway include
Shh, Ptch-1, Smoothened (Smo), glioma-associ-
ated oncogene transcription factors (Gli) and sup-
pressor of fused protein (Sufu) (see Figure 1).
In the absence of Shh, Ptch-1 is located on the
primary cilium and acts as a tumour suppressor,
constitutively repressing the G-coupled receptor
protein Smo. On binding of Shh, Ptch-1 moves in-
tracellularly and Smo is translocated towards the
primary cilium, removing the repression of Smo.
Uninhibited Smo promotes the importation of Gli
transcription factors into the nucleus. Gli proteins
9
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Review
www.dermatologyinpractice.co.uk
The genetics of basal cell carcinoma
Ptch-1 Smo
Sufu SufuGli
Shh
ShhPtch-1 Smo
Gli
1 2
3
4
5
Inactive Shh pathway Active Shh pathway
1. Shh ligand binds to Ptch-12. Smo relocates to primary cilium3. Uninhibited Smo promotes Gli4. Unbound Gli enters nucleus5. Gli activates transcription
Genetranscription
Gli = glioma-associated oncogene transcription factors; Ptch-1 = Patched-1; Shh = sonic hedgehog ligand; Smo = Smoothened; Sufu = suppressor of fused protein
� Figure 1. The sonichedgehog pathway
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
are bound by Sufu, the loss of which produces con-
stitutive activation of Gli.
The Gli proteins are effectors of the hedgehog
pathway, possessing DNA-binding, zinc-finger do-
mains which bind to consensus sequences on tar-
get genes, thus regulating transcription. Gli
activates multiple target genes which are key regu-
lators in cell cycle progression and differentiation.
Sporadic BCC tumours demonstrate loss of func-
tion of PTCH1 in 80–90% and SMO in 10–20% of
cases.5 BCCs have also been demonstrated to result
from constitutive activation of the SHH pathway
in both murine skin and human skin grafted to
mice.9 These findings underline the significance of
the SHH pathway in BCC tumorigenesis.
Support for the central role of PTCH1 mutations
in BCC tumorigenesis comes from a recent whole-
exome sequencing study where only PTCH1
was found to have a significant functional muta-
tion burden.10
Genome-wide association studies (GWASs) are
now allowing the identification of novel alleles as-
sociated with a risk of BCC.11 Combining GWASs
and gene expression genetics to identify biological
pathways associated with BCC has identified the
JAK-STAT signalling pathway as plausibly being
involved in BCC pathogenesis.12
Cellular origins of BCCs
The cellular origins of BCCs have long been
uncertain. In 1900, Krompecher first proposed
that these tumours arise from the basal cells
of the epidermis, though this was contested.13
More recently, studies using murine stem cells
with constitutively active Smo demonstrated
BCC formation following interfollicular
epidermal progenitor (IFE) cells being rapidly
reprogrammed into embryonic hair follicle
progenitor (EHFP)-like cells, prior to rapid up-
regulation and tumorigenesis. During experi-
ments, temporal up-regulation of the Wnt sig-
nalling pathway during tumorigenesis was noted
and, importantly, deletion of β-catenin prevented
tumour formation.14,15
Canonical Wnt/beta-catenin pathway
Many similarities exist between the hedgehog
and Wnt signal transduction pathways, both
being highly conserved, influential in embryo-
genesis, inactivated in most cells following devel-
opment, and key drivers in oncogenesis when
hyperactive.
β-catenin promotes transcriptional activation
and has a central role in the Wnt pathway. The
level of β-catenin is tightly regulated in the cy-
tosol, by being constitutively broken down via the
β-catenin destruction complex (BCDC).
Activation of the pathway is triggered by attach-
ment of the Wnt protein to Frizzled (Fz,) a G-cou-
pled receptor protein. Binding promotes BCDC
inactivation via Dishevelled (Dsh), allowing β-
catenin accumulation and gene transcription.
10
Review DERMATOLGY IN PRACTICE 2013; Vol 19 No 4
www.dermatologyinpractice.co.uk
� Basal cell carcinoma of the neck
� Basal cell carcinoma of the nose
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Genetic damage from solar radiation
UV light is a class 1 carcinogen and the primary
aetiological agent in the development of sporadic
BCCs. Whole-exome sequencing has demon-
strated proportionately increased levels of UV
signature mutations in PTCH1 and TP53.10
UVB damage occurs through a photochemical
reaction following direct UV absorption by DNA.
Damage to adjacent pyrimidines may produce
cyclobutane dimers (CBDs) and (6-4) pyrimidone-
pyrimidine (64PP) adducts. These photolesions
cause UV signature mutations, with cytosine being
changed to thymine, either singly or in tandem.16
UVA photons are less energetic and damage
DNA indirectly by the generation of reactive
oxygen species (ROS). ROS cause DNA strand
breaks and produce oxidative base damage.16
Recent whole-exome sequencing has shown
BCC to be the most mutated cancer, squamous
cell carcinoma (SCC) being the
second most mutated (75.8 and
33.3 mutations per megabit of
coding DNA, respectively). This
has led to the hypothesis that a
greater mutational burden in-
creases the antitumour immunological response,
leading to a less aggressive phenotype.10
UV-induced DNA damage normally results in
DNA repair (error-free and error-prone) or apop-
tosis; only very rarely does it lead to tumorigenesis.
Where DNA repair mechanisms are impaired in
conditions such as the rare autosomal recessive xe-
roderma pigmentosum (XP), skin cancer rates are
greatly increased, with a 2,000-fold increased risk
in homozygotic patients.17
Pathway inhibitors
Inhibition of the hedgehog pathway provides an
attractive therapeutic avenue as BCCs have been
shown to originate from its activation.
What is now recognised as hedgehog pathway
inhibition was first observed in sheep in Idaho in
the 1950s. During a time of drought, sheep grazed
on higher ground, ingesting the abundantly grow-
ing California corn lily (Veratrum californicum).
Subsequent progeny were observed to develop
craniofacial abnormalities ranging from mild mi-
crognathia to severe cyclopia and holoprosen-
cephaly. Extraction methods later established
cyclopamine (11-deoxojervine) as the teratogen,
which was subsequently discovered to act as a Smo
receptor antagonist.
Vismodegib is a first-in-class, orally bioavailable
inhibitor of Smo, which was licensed in August
2013 in the UK for the treatment of metastatic
BCC (mBCC) and locally advanced BCC (laBCC).
LaBCCs are tumours which have penetrated
deeply, have recurred, or are sited where conven-
tional treatments would be unfeasible or cause
considerable morbidity.
In the Phase II trial of a multicentre, interna-
tional, two-cohort non-randomised study, pa-
tients with laBCC (n=63) and mBCC (n=33) were
treated with 150 mg vismodegib daily until the ob-
jective response rate of a 30% reduction in size was
obtained. Results demonstrated significant re-
sponse in 43%, with complete response in 21% in
the laBCC group and a significant response rate of
30% in the mBCC group.5
All patients described side effects, with over 30%
describing myalgia, dysgeusia, alopecia, weight
loss and fatigue, which are considered to be class
effects of Smo antagonism. Grade 3 and 4 adverse
effects were reported in 43%, including fatigue,
dyspnoea, muscle spasm, QT prolongation and
asymptomatic hyponatraemia. A subsequent trial
in HBCNS again demonstrated
significant response, but 54% of
patients discontinued therapy
due to side effects.5
In laBCC, 5% of patients
demonstrated regrowth during
treatment.5 Elucidation of resistance mechanisms
remains sparse; however, a case report docu-
mented secondary resistance due to an SMO muta-
tion (D473) which decreased binding affinity.18
Rebound of tumour growth following cessation
of treatment has been documented.5 This may
occur as a fraction of cells remain quiescent and
evade apoptosis during treatment. Whether cell
destruction occurs concentrically or in a scattered
manner requires further investigation, as this will
affect its utility as a neoadjuvant treatment.
Further Smo inhibitors are currently being tri-
alled including LDE225 (erismodegib), IPI-926
(saridegib), LEQ506 and PF-04449913.
Upstream blocking of the hedgehog pathway
has been investigated with robotnikinin being de-
veloped as a macrocyclic molecule able to bind to
Shh protein. More recent developments starting
11
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Review
www.dermatologyinpractice.co.uk
� Constitutive activation of the sonic hedgehog pathway iscentral to basal cell tumorigenesis and may occur congenitally(as in basal cell naevus syndrome) or be acquired later in life.
� Recent whole-exome sequencing has shown basal cellcarcinoma (BCC) to be the most mutated cancer, squamous cellcarcinoma (SCC) being the second most mutated.
� Vismodegib is a first-in-class, orally bioavailable inhibitor ofSmo, which was licensed in August 2013 in the UK for thetreatment of metastatic BCC and locally advanced BCC.
Key points
Whole exomesequencing hasshown BCC to be themost mutated cancer
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
from robotnikinin’s structure found BRD-6851 to
be the most promising macromolecule; this was,
however, found to act as a Smo antagonist. 5E1,
an antibody targeting the epitope close to Shh–
Ptch-1 interaction, has been developed.18
Downstream blockade provides an exciting
avenue of current interest. Treatments being in-
vestigated include Gli antagonists (GANT 58 and
61) and agents impairing Gli acetylation and pri-
mary cilial function. Inhibition of the Wnt path-
way via β-catenin is also being studied, but this
may be challenging due to the molecule’s flat
polar surface, which engages in multiple protein–
protein interactions.
Conclusion
Advances in molecular genetics have given sub-
stantial insights into the pathophysiology of, and
risk factors associated with, BCC. The centrality of
the SHH pathway in BCC development is appar-
ent, but understanding downstream pathways
and crosstalk between pathways remains complex
and incomplete. Novel targeted pathway treat-
ments are emerging, but currently their clinical
use remains limited because they are associated
with frequent and considerable side effects �
Declaration of interestJohn T Lear has accepted honoraria for speaking at meetings by Leo, Galderma,Almirall, Astellas and GSK. Nicholas J Collier and Faisal R Ali have nothing to declare.
AcknowledgementThe authors acknowledge the support of the Clinical Photography Department, Salford Royal NHS Foundation Trust.
References1. Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003, 327: 794–798.2. Roewert-Huber J, Lange-Asschenfeldt B, Stockfleth E, Kerl H. Epidemiologyand aetiology of basal cell carcinoma. Br J Dermatol 2007; 157: 47–51 .3. Karagas MR, Greenberg ER. Unresolved issues in the epidemiology of basalcell and squamous cell skin cancer. In: Mukhtar H (ed). Skin Cancer: Mechanismsand Human Relevance. Boca Raton, USA: CRC Press, 1995: 79–86.4. Domarus H, Stevens PJ. Metastatic basal cell carcinoma: report of five cases andreview of 170 cases in the literature. J Am Acad Dermatol 1984; 10: 1043–1060.5. Ali FR, Lear JT. Systemic treatments for basal cell carcinoma (BCC): the adventof dermato-oncology in BCC. Br J Dermatol 2013; 169: 53–57.6. Gorlin RJ, Goltz RW. Multiple nevoid basal cell epithelioma, jaw cysts and bifidrib: a syndrome. N Engl J Med 1960; 262: 908.7. Jones EA, Sajid MI, Shenton A, Evans DG. Basal cell carcinomas in Gorlin syn-drome: a review of 202 patients. J Skin Cancer 2011; 2011: 217–378.8. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number andpolarity in Drosophila. Nature 1980; 287: 795–801. 9 Colmont CS, Benketah A, Reed SH et al. CD200-expressing human basal cellcarcinoma cells initiate tumor growth. Proc Nat Acad Sci 2013; 110: 1434–1439.10. Jayaraman SS, Rayhan DJ, Hazany S, Kolodney MS. Mutational landscape ofbasal cell carcinomas by whole-exome sequencing. J Invest Dermatol 2013; 276:[Epub ahead of print].11. Hongmei N, Mousheng X, Kraft P et al.Genome-wide association study iden-tifies novel alleles associated with risk of cutaneous basal cell carcinoma andsquamous cell carcinoma. Hum Mol Genet 2011; 20: 3718–3724.12. Zhang M, Liang L, Morar N et al. Integrating pathway analysis and geneticsof gene expression for genome-wide association study of basal cell carcinoma.Hum Genet 2012; 131: 615–623.13. Mcfarland J, Ciccone EF, Gelehrter J. On the dysontogenetic origin of basal-cell carcinoma. Am J Cancer 1935; 25: 273–281.14. Youssef KK, Lapouge G, Bouvré et al. Adult interfollicular tumour-initiatingcells are reprogrammed into an embryonic hair follicle progenitor-like fate dur-ing basal cell carcinoma initiation. Nat Cell Biol 2012; 14: 1282–1294. 15. Tan DMT, Barker N. Stem Cell reprogramming as a driver of basal cell carci-noma. Nat Cell Biol 2012; 14: 1246.16. Ikehata H, Ono T. The mechanisms of UV mutagenesis. J Radiat Res 2011; 52:115–125.17. Lear JT, Hoban P, Strange RC, Fryer AA. Basal cell carcinoma: from host re-sponse and polymorphic variants to tumour suppressor genes. Clin Exp Dermatol2005; 30: 49–55.18. Cucchi D, Occhione MA, Gulino A, De Smaele E. Hedgehog signaling pathwayand its targets for treatment in basal cell carcinoma. J Exp Pharmacol 2012; 4:173–185.
12
Review
www.dermatologyinpractice.co.uk
�Your views on Dermatology in practice
The majority of responses were from GPs (27.3%),closely followed by nurse specialists (24.2%). The restof the respondents were made up of other nurses(12.1%), dermatologists (9.1%) and GPs with a specialinterest in dermatology (6.1%).
Over half of respondents read all or most of eachissue and it is also used for reference and to aidtraining (see Figure 1).
Informative and influential
DIP is considered by 46% of respondents to be ‘veryuseful’, with a further 25% finding it ‘extremely useful’.The journal is therefore considered a more usefulsource of information than other medical journals orcolleagues, which were rated as ‘very useful’ by 43%and 36% respectively.
Everyone who took the survey agreed that DIPwas of some, or great, benefit. Over 74% agreed or strongly agreed that the journal maysometimes influence the way in which they care for their patients.
Over half of respondents are happy to access thejournal online as a PDF, but 62% would also like a fulltext version and 39% would like to read DIP in an app.
Additionally, a large proportion of therespondents – 71.4% – would be interested incompleting online CPD modules if they wereoffered on the DIPwebsite �
Here, we report on the results
of the reader survey we ran
earlier this year.
60%
50%
40%
30%
20%
10%
0%I read allor mostof each
issue
I readcertainarticles
only
I use itas a
resource forreference
I use it toaid my
treatmentof patients
I use itto aid mytraining
I use itto trainothers
18.8%25.0%25.0%
43.8%
34.4%
53.1%� Figure 1.Reading habits
Congratulations to Marie Retzback, Nurse Specialist in West Suffolk, who was the lucky winner of a Kindle Fire in the prize draw.
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
T H E J O U R N A L O F T H E E U R O P E A N A S S O C I A T I O N F O R P A L L I A T I V E C A R E
������������� �� ��������� �����*/"( ",��"!"( ",��������*'.("�����.( ",�� 000�"&+!�".�!*(
���������� ���!������"&�+!��&�/+����0��)*�
#&'.&��&��,&#&'.&�,&#&'.&*�������������������!����-#�
����������������� ����� ��**"*+����0"& �1 +!���,))�&+�*"+,�+"'&�"&��$�&��)*
�,+!�&�*"���%�������"&�(�$$"�+"-����)������������������)!���#��#���&������&'/#���)!!������&����'"�(��#���&(�)-'"�#'
���� ���'%%�&+�)0�'&��**"*+����0"& �1 +!���,))�&+*"+,�+"'&�"&��$�&��)*��,+!�&�*"���%�������"&�(�$$"�+"-����)��
�����������������$#����#��!!
���������������������� ����� �����#*($����1 ��!'*("������"��+���+'�
+��&� �)*��&��0',& ���,$+*�"&���%(*!")���������������� �'!�-��&$$
��������������� ���������� ���**�&+"�$����+,)�*�'����()�*�)"�"& �"&�
(�$$"�+"-����)��+!��-"�.*�'���&��,*�)*����������������(�%��#���&���#����,���('$#
������������� ���� ���������������� ���!�+�(�$$"�+"-����)����&��'��')�%'+')�
&�,)'&���"*��*��(�+"�&+*��&��+!�")���%"$"�*�����������������*����!�*�&��#����"�&��$)#
���������������������� ���)�&��*��!�$�'&��)"+"*!�*'�"�$�.')#�)��
�,)'(��&�(�$$"�+"-����)��$����)��"&+�)&�+"'&�$(*0�!'*'�"�$���)���/(�)+
�����������������*����!�*��&���#����"���&(�
������������� ����������������� ��� "� &'*"& ��0"& ��"&���&��)�(�+"�&+*�1
��*0*+�%�+"��$"+�)�+,)��)�-"�.����������������(����#��-��"0!!�&���&�#.�'����$"��'�#���#���((��������&�� �((�#��
��!����!���$���#���! �&��#����''�"$��$'(�#(�#�
��� ����� ������������������������&!$'���#(�#$��#����*����!�&
������������������� ������ ���,)��%�++�)*�1 !'*("�����)��"&�+!��(�+"�&+�*�!'%������������������)!����$$#
������������������� ����� ����$$"�+"-����)��)�*��)�!�"&���*+�)&��)"������������������*����"�'�#�$�������&�����$+�!!���!�#���&�) ��������&���&��#��
�""�#)�!� )-�&� ���#�����(����#����$+�!!
���� ��������)$0���*��)�!�)�.�)�������1 $''#"& ����#����������������$����"��$��#
�������������������������������� ���&+�)&�+"'&�$��!"$�)�&�*���$$"�+"-����)����+.')#
.')#"& �+' �+!�)�+'�*+'(��!"$�)�&�*�*,���)"& ����������$�#���&'($#���)���$)���&���)!����$+#�#����)'��� $'���#����&��&���(��!
��� �*)�-$"�%)-",)"-Visit www.ejpc.eu.com to read the current issue online or to access the EJPCarchive of past issues
�������������������������� masterclass������� �'%($"��+���!'%���"*�!�) ��'���& +�#"���'��,)�+��*%'#�)�&���"& �'/0 �&�+!�)�(0��$&+�##���(���#'
���������������� ����0��)�'$��%�&� +�#"����/(�)"�&�"& ���&,%��)�'��()'�$�%*��**'�"�+���."+!���)#"&*'&�*��"*��*���##��)"�
� Participatory Research in Palliative Care – Actions and Reflections��"�!!��)''��#� Palliative Medicine in the UK c.1970–2010�$&�##������!�-
+�#"��
+�#"��
�������� ������� ��������� �)))���%"��$�( ���������������������������
The British Journal of RenalMedicine is sponsored by
an educational grant fromBaxter Healthcare Ltd. Baxter
has no editorial input into thispublication other than where
explicitly indicated.
� Scan the code onyour smartphone tovisit the website
�������������� ��!�%!#$��!#��#$���������������!����'
������������������������� �����"�)��(�$��� �&"��%��! �%���"�%�!�� �$�$�� ���� ����� %
�������������!#�������"�������$������
������������������� ��!�)"��#���)�� �� ! �
����#� ���%!�"#�$�#���������� �$�� ���
����������$"�������� ������������'
������������������������ ��'�#�!�� ��%���%��� ����
������ ��$�!����"���� %� ��� !�%&# �������!����)$�$"#!�#����
������������(���#���� �����'���������� ���#!�
������������������������� ����%���%�����)�"�%�� %$
��!&%�%�������$%#)��!#���#����� �)���$��$�$
��������������������
�������������������������� %��)� ��� ���� ��� �
��"#�$$�! �! �� � ��& �%��������� $�'�������&�'���������������������
�������������������������� ��"�#% �#$��"��""#!����
%!�%#� $"�� %�"#�"�#�%�! �� '!�'� �������#� ��)!& �"�!"���� ��%���#��������$
�����������!����%�"����!"#'��'����"�����������""������$������'
�����������������������������#�� �#�#���%��#�")��!#
�#%�#�!'� !&$���$%&��$�������������#�'���� ��'����������&����'��
�������!�����������&������#������"'����������������
�%��#����%&#�$
���%�'�&����#�!��$���'*�����'�$#�!����#�*� ���%�'�$#����$!��*�"�''�%&
�����#�*���&��%�����
AUTUMN 2013 VOLUME 5 NUMBER 3
Comment 3 The need for knowledge Nikos Myttas
Investigation 4 ADHD and delayed
puberty: is there a link? Diluki Kevitiyagala and Fiona Finlay
Diagnostics 7 Executive function as an
ADHD endophenotype Tony Steffert and Beverley Steffert
Practical resources10 What schools need
to know about ADHD Andy Bloor
Abstract watch13 Topical debates and new
therapeutic research Nigel Humphrey
Investigation14 Primary school
teachers’ ADHDknowledge: a study
Angel Adams, Alfred Perera and Radha Bhat
ADHDin practice www.adhdinpractice.co.uk
ADHD in practice is sponsored by an unrestricted educational grant from Shire AG.Shire has no editorial input into, or control over the content of, this publication.
Other features18 Book review19 HADD
� Scan the code on your smartphone to visit the website
������������� ������ �����������
����������� �����������������������������
������������������ ������������� ����������� ����������������������
�����������������!����������������
������������ ����������������
� � �������� ������ �����������������������������������������
��������� ����
������������������ ��� ����������
��� ��������� ���������� �����
��������������������������� ���!����������������������������������������������������������
��������� ��� �������������
����������������� ��� �
����������������������������������������
����������in practice
���������� ���������������� �����������!����������������
�������������� ����� ������������!��������������"���������
BRITISH JOURNAL OF2011 VOLUME 33 NUMBER 4
SEXUAL MEDICINE
Sexually transmitted infections and the eye 4
Spot and treat chlamydial eye infection in adults 9
The science behind human papillomavirus vaccines: part 2 12
St Stephen’s AIDS Trust funds research to improve care 15
HRT: one size does not fit all 16
Comment 3 Reader survey 11 Diary dates 18 The Hicks files 19
www.bjsm.co.uk
�� �� �� �
The lion’s share of the discussion injournals about vaccination focuses onvaccinology – the scientific aspects ofvaccines and vaccination policy. Howbest to deliver high vaccination coverageis, relatively speaking, a neglected topic.Although recent national guidance
describing standards for the delivery ofour national vaccination programme islaudably comprehensive,1 it does notreadily answer the question as to whatinterventions make the big difference inimproving coverage rates. Many of us have been inspired by the success ofcolleagues at the Heart of BirminghamTeaching Primary Care Trust.2 InManchester, we have borrowed theirpractical ideas, but also been bolsteredby their uncompromising attitudethat high vaccination levels can
be delivered in ‘difficult’ populations: ‘Ifservices in your patch are failing to reachthe communities you serve, [then] … yourservices are sub-standard!’.The articles in this issue of Vaccines in
practice show how local areas improvedtheir services, often startlingly so. How did they do it? Various approaches
are described, including a healthpromotion initiative and domiciliaryinterventions, but a clear theme is thatbetter organisation of operational systemsis fundamental. That was the key lessonfrom Birmingham, and an excellent reviewfrom London reinforces that message.3 Thebasis of high coverage is an effectiveadministrative system for call/recall,4 whichcan increase coverage by up to 20%.5
Data cleansing is the vital first stage. The review from London rightly concludedthat, ‘[accurate data] underpins all otherinterventions and should be the priority’.6
This is particularly important in urbanareas because of high populationtransiency. In a cohort of children in Manchester, only 51% of thoseborn in Manchester still lived there by the age of three
to five.7 Some hadmoved 30 times
by the age of three.
Many children will have a) beenvaccinated but not recorded as such in thecentral child health information system, orb) moved out of the area. Data cleansingaddresses these main causes of inaccuratedata and, although no additional childrenare vaccinated directly as a result, thisallows the creation of a ‘fail-safe’ databaseof children who have truly missedvaccination(s). Defaulters can then bemore efficiently targeted (‘tail-gunned’).2
Sadly, the authors have not been able toevaluate the cost-effectiveness of theirinterventions, although costs are provided.These are cash-strapped times, but it isclear that improvements should not becostly. The trick will be finding the effectivepractical changes needed in your area toimprove routine vaccination coverage thatare the least expensive. Public healthleadership will be needed, as will strongproject management, to make change. Wehope you will be inspired to do just that �
References1. Health Protection Agency. Quality criteria for an effectiveimmunisation programme. www.hpa.org.uk/webc /HPAwebFile/HPAweb_C/1317135275261 (last accessed 20/11/12)2. Heart of Birmingham Teaching Primary Care Trust. WorkingSmarter, Improving Performance.Heart of BirminghamTeaching PCT, 2006.3. Cockman P, Dawson L, Mathur R, Hull S. Improving MMRvaccination rates: herd immunity is a realistic goal. BMJ 2011;343: d5703.4. Jacobson Vann JC, Szilagyi P. Patient reminder and patientrecall systems for improving immunization rates. CochraneDatabase Syst Rev 2005; 20:CD003941.5. Crowcroft NS. Action on immunisation: no data, no action.Arch Dis Child 2009; 94: 829–830.6. Healthcare for London. Childhood Immunisation Programmesin London PCTs: Early sharing of good practice to improveimmunisation coverage.www.londonhp.nhs.uk /wp-content/uploads/2011/03/Childhood-Immunisation-in-London-Sharing-Good-Practice.pdf. (last accessed 20/11/12)7. Davies GM, Boothman NJ, Duxbury JT, Davies RM, BlinkhornAS. An investigation of non-participation in health promotioninterventions and its impact on population level outcome. IntJ Health Promot Educ 2008; 46: 107–112.
December 2012 Volume 5 Number 3www.vaccinesinpractice.co.uk
� � � � � � � � � � �
��������
Vaccines in practice is supported by an unrestrictededucational grant from Pfizer Vaccines
Kevin PerrettMB ChB FFPH Consultant in Public Health Medicine -Health Protection Adam Gowland BA(Hons) ImmunisationPromotion Project Manager, Public Health Manchester
����������������������������������������������
� Scan the code onyour smartphone to visit the website
� ����������������������� �����
� �������� � ����� � ������ � ������ �� ���������������������
JOSH
SHE
R/SCIENC
E PH
OTO LIB
RARY
Please circulate
Managing painWinter 2011 Volume 2 Number 4
www.mpip.co.ukin practice
Meda Pharmaceuticals Ltd provided an educational grant tosupport the production and distribution of this publication.Meda Pharmaceuticals Ltd had no editorial control and its involvement is limited to the review of the articles
on pages 1–4 for balance and medical accuracy.
Name Name
Gastroprotection withNSAIDs – how can wemake things happen?
The National Institute for Health andClinical Excellence (NICE) guideline onosteoarthritis (OA) (see Box 1) is one ofNICE’s better pronouncements.1 The adviceon the use of a proton pump inhibitor (PPI)with a non-steroidal anti-inflammatorydrug (NSAID) or cyclo-oxygenase-2 (COX-2) inhibitor could not be morestraightforward. Nor is it news – theevidence has been available for years andvarious sets of guidelines have said thesame for at least a decade. And yet thisguideline on using a PPI with an NSAID islargely ignored. Moreover, even when aPPI is prescribed with the NSAID, manypatients fail to adhere to the prescription.
What are the reasons behind this? Anin-depth study of US physicians suggestedsix possible reasons.8 These included:� Lack of familiarity with guidelines� Perceived limited validity of guidelines
� Limited applicability of guidelinesamong specific patients
� Clinical inertia� Influences of anecdotal experiences� Medical heuristics, often derived from
physicians’ assessments� Personal opinions/clinical experiences.
‘Getting your head around the problem’We may have to be more specific and boilthe – very considerable – evidence downto some simple bullet points. � Patients with chronic pain have a fairly
awful quality of life (QoL).� Patients with untreated, or poorly
treated, pain will lose an importantportion of their life because of it.
� Patients want their pain to go away, orto be mild at worst, so they cancontinue to carry out normal activities.
� Many analgesic drugs and othertreatments, including lifestyle
Andrew Moore MA DPhil CChem FRSC FRCA DSc Directorof Research, Pain Research Unit, University of Oxford
�� � �� ����������������� � ����������Page 4
Advice on prescribingNSAIDs with PPIs islargely ignored
In this issue ...
Comment: The value ofguidelines 3Dominic Aldington
Neuropathic pain guidelines: an overview 5Alia Darweish and Murli Krishna
Commissioning painmanagement services 9Norman Evans and Shailen Rao
Diary dates 10
Reader survey 11
Chronic hepatitis B (CHB) remains aglobal healthcare challenge. Despite theavailability of a vaccine for almost 40years, an estimated 350 million peopleare chronically infected worldwide andthe complications of persistent infection,namely cirrhosis and hepatocellularcarcinoma (HCC), account for roughly onemillion deaths per year.1,2
Two treatment strategies exist for the management of CHB: interferon-alfa(IFN-α) (standard or pegylated) andnucleoside/nucleotide analogues (NUCs).The oral antiviral agents, or NUCs, arewidely employed in the treatment of CHB;they have an excellent safety profile andpotent anti-hepatitis B virus (HBV) efficacyin adults. However, both these treatmentstrategies are suboptimal, in terms of HBVeradication, in the majority of patients. Forthis reason, new approaches to HBVtreatment are needed to maximiseresponse and to approach a disease ‘cure’.Recent debate has focused around the
Patrick Kennedy MB BCh BAO BMedSci MRCP MDSenior Lecturer and Consultant HepatologistUpkar Gill MB ChB BSc (Hons) MRCP PGDip Specialist Registrar andClinical Research Fellow in Hepatology, Centre for DigestiveDiseases, Blizard Institute, Barts and The London School ofMedicine and Dentistry, Queen Mary, University of London
������������ ����
�� ��B is not for boring! �Alastair Miller
����Resistance testing in hepatitis C virus infection –an overview �Patricia Cane
����When should I test for hepatitis E virus? ��Theresa Hydes and Kathryn Nash
����������Diary dates �Resources ��
������������� � � � � � � � � � � � � �
� � � � � � � � � �
������� ��������������
��������������������� �����������
Printed with the support of an educational grant from Roche Products Limited. Roche has no editorial control of this publication.
Printed with the support of an educational grant from Gilead Sciences Ltd. Gilead has no editorial control of this publication.
� Scan the code onyour smartphoneto visit the website
�������������� �����������
�� �������������������
� �����page 5
�Molecular model of hepatitis B virus
MICHAEL FREEMAN/MEDNE
T/CORBIS
Myeloid disorders in practice is co-sponsored by an unrestricted educational grant from ShirePharmaceuticals. Shire has no editorial input into, or control over the content of, this publication.
Myeloid disorders in practice is co-sponsored by an unrestricted educational grant from Celgene. Celgene has no editorial input into, or control over the content of, this publication.
###���������!�
����������� ��!������!������
����������
� ��������������
������ ��������� ���������
�������������������������������������
� Scan the code on your smartphone to visit the website
������������������������������������������������������� ������#����������%� ������
�%����%�������������!� �������!��������&#�� �� ����������������#���$��� ���� ����! !��
�������������������#
���������������������������� ����� ������� �������
�����������������������"��#���� ��� ��� ��� ��� ������"�������
���� ����������$������ ��������#������� ���������������� � �����%�� ��������������! ����
�������������#����#�������#�������� �������� ����������
��������������������������������������� ����
�����!��� ��!������������������������������ �����%���������������
��������������� � ����!���� �%�!�����������!��#� ���� �� �������������"�����!�"�"����� ��������! ���%��������!������
����������������������
�������������������� �������������������������
������������������������������������������� �������������"��"������
������%������������ �"���������� ������� �������������������������� ����� ��������� ���� ����!������
������������������"����#��������� ���������������!����������#
������������������������������ ���������������
�������� �����������������������#� �����������������%����#�����#� ��
����!������������������#� �� �������������������������� ����%���!��
����������������������������������� ������������������������������#
Thrombus is funded by an educational grant from Boehringer Ingelheim Ltd
���������������� � ������ ����������������
�������abcd
The Clinical Leaders of Thrombosis (CLOT)is a specialist interest group consisting ofapproximately 450 multidisciplinaryhealthcare professionals (HCPs), who havedirect patient contact, working in the fieldof haemostasis and thrombosis, mainly inthe UK. The group’s aim is to shareknowledge and experience, and facilitatelearning to support members in thedelivery of high-quality care. CLOT alsoaims to shape future services and advancethe boundaries of healthcare delivery.
����Members of CLOT highlighted the need forwritten guidance on counselling patientswho have been prescribed oral directinhibitors (ODIs). As individual HCPs, CLOTmembers have many requests for writtenguidance on the subject, with reference torelevant publications, and want to deliverproactive patient-focused care. They felt thatuntil confidence in the use of the new drugshas developed among HCPs, the CLOTgroup is ideally placed to provide andpromote this information as an informedresource for those delivering care.1
����� ��At the annual meeting in October 2012, an‘advancing practice’ workshop was held. Theworkshop attendees split into discussiongroups looking at national, regional, local,and pharmaceutical companyrecommendations for the use of dabigatran and rivaroxaban (see Box 1),2–5
the two drugs licensed for therapeuticanticoagulation in 2012.2
The recommendations for each wereconsidered, opinions gathered and concernsshared. These were used as the basis for thecounselling checklist. At a national level,standardisation by the National Institute forHealth and Care Excellence,3,4,6 the BritishCommittee for Standards in Haematologyguidance1,7 and the National Patient SafetyAgency (NPSA)recommendations1,8 wereconsidered. Regionally, policies andguidance from the Central ManchesterClinical Commissioning Group, East ofEngland Priorities Advisory Committee andCoventry and Warwickshire PrescribingCommittee were shared. At a local level,policies from Cambridge UniversityHospitals NHS Foundation Trust and CentralManchester University Hospitals NHSFoundation Trust were considered. As a result, issues for HCPs to consider
when counselling this patient group wereidentified. The workshop attendees decided,by a majority vote, that the newanticoagulants should be referred to as ODIsto avoid inconsistency and confusion.
����������������������The counselling introduction should include:� Checking the patient’s personal details
and an introduction to the HCP � An explanation of the purpose of
anticoagulant therapy, what types oftherapy are available and why thetreatment is appropriate for the patient.The following information must be
confirmed with the patient: � The name of the oral anticoagulant
prescribed � The date treatment commenced and
Caroline Baglin RGN BSC Nurse Consultant –Thrombophilia and Anticoagulation, Addenbrooke’s Hospital, Cambridge
�������� ����������� ��� ��������� ��
���������������
����������������������������������������� ������������������������� ����
������������ ����
��������� ���� �� ���������Peter Rose
����������� �� ������������������������ ���������������� ���� � �����Greg Fell
� � ������������������������� ��� ���������������������Juliane Kause, Tracy Graham and Judith Effeny
���������������������������� ����������������������
�� ������������������ ����� �
� Scan the code with your phone to visit Thrombus online
HaywardMedical Communications w w w. h a y w a r d . c o . u k
What can we do for you?
… just some of thecomments from healthcare professionals about ourrange of specialist journals
www.haywardpublishing.co.uk
well written beneficial in practice excellent reviews clear and well
presented very helpful and informative good range of articles easy to
read topical I like the format practical advice on management interesting
and informative nice clear summaries very relevant materials excellent
good layout concise very useful I learnt something new today spot on
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Colin MortonMD FRCP ConsultantDermatologist, ForthValley Royal Hospital,FalkirkMegan MowbrayBSc(Hons) FRCP MDConsultantDermatologist, QueenMargaret Hospital,DunfermlineColin ClarkFRCP ConsultantDermatologist,Glasgow RoyalInfirmary, GlasgowGirish GuptaFRCP ConsultantDermatologist,Monklands Hospital,AirdrieRobert HerdMSc MD FRCP ConsultantDermatologist,Western Infirmary,GlasgowColin FlemingBSc(Hons) FRCPConsultantDermatologist,Ninewells Hospital,Dundee
Several new therapy options have recently be-
come available for the management of actinic
keratosis (AK). Most of these treatments are in-
tended to treat small, or large, areas of sun-
damaged skin – recognising the importance of
field cancerisation, where skin adjacent to
AK may contain dysplastic
cells, while other therapies are
best suited for individual le-
sions. It is impossible to predict
which AK might develop into
invasive squamous cell carci-
noma (SCC), so guidelines recommend wide-
spread treatment of AK. As approximately 20%
of the UK population over 60 years of age will
have at least one AK, with prevalence increas-
ing with age, this represents a considerable
therapeutic challenge in an era of restricted
healthcare budgets. In this article, we briefly re-
view the therapies now available and propose
a practical approach to treatment choice.
Appearance and prevalence
AKs are common skin lesions, typically presenting
as reddish-brown macules or plaques, with a vary-
ing amount of hyperkeratotic scale (see Figure 1).
They arise in areas of chronic sun exposure – on
the face, forehead, scalp, ears, neck, upper chest,
arms and dorsum of hands, and are more com-
mon in individuals with fair skin. They can range
from a few millimetres to 2 cm in diameter and
may be solitary or multiple (see Figure 2). AK usu-
ally develops as a consequence of cumulative sun
exposure, although it can be induced by iatrogenic
phototherapy, X-rays and radioisotopes. In the UK
and Ireland, 19–23% of individuals over 60 years
have at least one AK.1
AKs are typically divided into three subtypes, re-
flecting thickness: thin/mild (better felt than
seen); moderate (easily seen and
felt); and thick.2 There are a few
differential diagnoses for AK, in-
cluding seborrhoeic keratoses, but
the most important one is SCC.3
The diagnosis is usually made on
clinical appearance although a biopsy should be
considered where there is diagnostic doubt.
Why treat AK?
Recently updated European guidelines encourage
us to classify AK as early in-situ SCCs in view of the
recognition of the genetic similarities between AK
and SCC and the observation that 60–80% of
SCCs arise within, or close to, existing AKs.4 As it
is currently not possible to determine which le-
sions may transform, strategies to promote treat-
ment of all lesions are recommended.
Although often observed as occurring as single
lesions or in small clusters, AKs are increasingly
recognised as arising in a setting of field canceri-
sation, where adjacent skin may also contain dys-
plastic skin cells, with increased potential for the
development of more AKs and other non-
melanoma skin cancers (see Figure 3).5 Fortu-
nately, for immunocompetent individuals, the
risk of an individual AK transforming into an SCC
is small, with 15–25% spontaneously clearing over
a one-year period – although 15% of regressed le-
sions have been observed to recur after 12
months.6,7 Many AKs persist without progression.
It is estimated that an individual with an average
of 7.7 AKs has a 10% probability of at least one
transforming within a ten-year period.8 The risk of
developing AK is around 250-fold higher for pa-
tients on long-term immunosuppressants, with a
higher proportion of these AKs developing into
SCCs.9 In addition to the risk of progression, AK
can cause considerable cosmetic concern to pa-
tients, as well as discomfort.
Who to treat?
Guidelines from the British Association of Derma-
tologists (BAD) indicate that treatment of AK is not
14
Therapeutics DERMATOLGY IN PRACTICE 2013; Vol 19 No 4
www.dermatologyinpractice.co.uk
Update on the treatmentof actinic keratosis
� Figure 1. Solitarymoderately thick actinic keratosis
AK usually developsas a consequence of cumulative sunexposure
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
universally required1 (guidance from the Primary
Care Dermatology Society is in agreement with
this10), advising that patients with a small number
of lesions might not benefit from treatment, espe-
cially if life expectancy is reduced. BAD recom-
mends clinical judgement to discern lesions and
patients at increased risk, with the option of no
treatment, or palliation with emollient to reduce
discomfort when appropriate. In the most recent
guidelines, issued by the European Dermatology
Forum, a stronger recommendation for treatment
is made, with the decision influenced by site of the
disease, extent of the disease, the patient’s age, co-
morbidities, evidence of previous skin cancer and
presence of immunosuppression.4
Who should treat?
Management pathways developed by NHS Scot-
land and the Scottish Dermatological Society rec-
ommend treating AK in primary care, except
where there is diagnostic doubt; if the lesions are
painful or rapidly growing; if there is extensive
solar damage; or in immunosuppressed patients.11
The National Institute for Health and Care Excel-
lence guidance states that all GPs are expected to
recognise, and make management decisions on,
patients with pre-cancerous skin lesions.12
Treatment options
Therapies are either lesion-specific, for single
and/or few lesions, or field-directed, to manage pa-
tients with multiple lesions where field cancerisa-
tion is more likely to be present. There is a shift
from viewing AK as low-risk, individual lesions, to
considering them akin to icebergs, indicative of an
area of surrounding sun-damaged skin at in-
creased risk of cancer – with a strong focus on field
therapies in a European consensus treatment al-
gorithm.13 Treatments are either ablative (such as
curettage, surgical excision and cryosurgery) or
topical (such as 5% fluorouracil, 5% imiquimod,
3% diclofenac in hyaluronic acid and methyl
aminolevulinate photodynamic therapy). We
focus on the therapies most accessible to practi-
tioners in the UK, with brief discussion of new
therapies; for example, ingenol mebutate, 0.5%
fluorouracil combined with 10% salicylic acid,
3.75% imiquimod and nanoemulsion aminolevu-
nic photodynamic therapy. Therapies such as
chemical peels, topical retinoids and laser therapy
are not commonly used as primary treatments for
AK in the UK.
Surgical excision of AK is not usually required
and is only performed if invasive SCC is sus-
pected. Curettage or cryotherapy are commonly
performed for AK, although they are now less
commonly practised in primary care. Curettage
remains a useful option for thick, hyperkeratotic
lesions, while cryotherapy is a useful option if
there are only a few lesions, or if they have failed
to respond to topical therapy. However, patients
need to be warned of the risk of pigmentary
change and scarring.
A detailed comparison of therapies is beyond
the scope of this article, but a recent Cochrane
15
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Therapeutics
www.dermatologyinpractice.co.uk
� Figure 2. Multiplefacial actinic keratoseswith scarring followingprevious cryotherapy
� Figure 3.Squamous cellcarcinoma surroundedby multiple actinickeratoses
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
review of interventions in AK concluded that,
for individual lesions, photodynamic therapy
appears more effective and has a better cosmetic
outcome than cryotherapy.
For field-directed treatments,
diclofenac, fluorouracil, im-
iquimod and ingenol mebutate
had similar efficacy, but their as-
sociated adverse events and cosmetic outcomes
are different.14 Key information about the topical
therapies currently available in the UK is shown
in Table 1.15,16
Recently approved topical treatments
Ingenol mebutate
Ingenol mebutate (Picato® [LEO Pharma]),
derived from the white sticky sap from the plant
Euphorbia peplus, appears to work both by rapid
cell necrosis and specific neutrophil-mediated an-
tibody-dependent cellular cytotoxicity. Two
strengths of this fast-acting prod-
uct are available: a 0.015% gel, for
use once daily on the face and
scalp for three consecutive days,
and a 0.05% gel to be applied
once daily on the trunk and extremities for two
consecutive days. Pooled results from four pivotal
trials show that the 0.015% gel cleared all
face/scalp AK in 42% of patients (83% of all le-
sions).17 The 0.05% gel cleared all trunk/limb le-
sions in 34% of patients (75% of all lesions). Local
skin responses (namely, erythema, flaking/scal-
ing, crusting, swelling, blistering or ulceration)
are commonly observed, peaking after comple-
tion of therapy.
16
Therapeutics DERMATOLGY IN PRACTICE 2013; Vol 19 No 4
www.dermatologyinpractice.co.uk
Table 1. Topical therapies for AK – recommended protocols, precautions and field use15,16
Therapy Protocol Precautions Field limitDiclofenac 3% gel (Solaraze®, Twice daily for 60–90 days Usually well-tolerated, occasionally causes a rash Max 4 g/application (as 0.5 g Almirall) covers 5 x 5 cm, max area 200 cm2)
5% fluorouracil (Efudix®, Once or twice daily for 3–4 weeks. Normal response is an early and severe Total area of skin being treated at Meda) Facial lesions usually respond quicker than inflammatory phase (usually in the second week any one time should not exceed
those on trunk/legs. Lesions on hands/ of application), then necrotic phase, followed 500 cm2
forearms respond more slowly by healing
0.5% fluorouracil combined Once daily to slightly palpable and/or Peel off existing coating before re-application. Total area of skin being treated at with10% salicylic acid moderately thick hyperkeratotic AK. Response Apply with brush applicator any one time should not exceed (Actikerall®, Almirall) can be seen from 6 weeks. Optimal effect may 25 cm2
not be evident for up to 8 weeks after cessation(only experience of use on face/scalp)
Imiquimod 5% (Aldara®, Apply three times a week to AK on face or Apply prior to normal sleeping hours, wash off Max recommended is 1 sachet, Meda) scalp for 4 weeks. Assess after a 4-week interval, after approximately 8 hours. Local inflammatory limit to ~25 cm2
repeat cycle if required reactions are common. There is an association between clearance and intensity of reaction. Advise rest period of several days if inflammationsevere. Flu-like symptoms are uncommon
Imiquimod 3.75% (zyclara®, Apply once daily before bedtime for two Local inflammatory reaction common. Rest period Up to 2 sachets, approximately Meda) treatment cycles of 2 weeks, each separated if required. Flu-like symptoms are uncommon 200 cm2 (whole face or scalp)
by a 2-week interval
Ingenol mebutate (Picato®, Once daily for 3 consecutive days to AK on face Local skin responses are common. Erythema, 1 tube covers 25 cm2
LEO Pharma) 150 µg/g gel and scalp (store in refrigerator at 2–8˚C) flaking/scaling and crusting typically occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion, resolving within 2 weeks
Ingenol mebutate (Picato®, Once daily for 2 consecutive days to AK on trunk Local skin responses are common, as with 1 tube covers 25 cm2
LEO Pharma) 500 µg/g gel and extremities (store in refrigerator at 2–8˚C) 150 µg/g, but can take up to 4 weeks to resolve
PDT (Ameluz®, Biofrontera Ameluz is new nanoemulsion of 5-ALA, Single treatment, repeat at 3 months if required, Apply to lesions and 5–10 mm ofor Metvix®, Galderma) Metvix is methylester of 5-ALA to AK on face/scalp (applied under occlusion for surrounding skin
3 hours before illumination with red light).Only to be administered by healthcare professionals trained in PDT. Pain/burning sensation is commonduring PDT. Erythema common after treatment andscab formation
5-ALA = 5-aminolevulinic acid; AK = actinic keratosis; PDT = photodynamic therapy
Patient preferenceshould drive thefinal choice
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Imiquimod 3.75%
A new 3.75% formulation of imiquimod
(Zyclara® [Meda]) offers the advantage that it
can be applied to larger areas of the skin, such as
the complete face, in a simplified application
protocol. Complete clearance of all AKs was
achieved in 36% of patients (82% of baseline
lesions) in a pivotal trial, with subclinical lesions
becoming visible during application and also
responding to treatment.18 The treatment ap-
pears generally well tolerated, although ery-
thema and scaling/crusting are commonly seen,
with about 10% of patients likely to require a rest
period during treatment.
0.5% fluorouracil plus 10% salicylic acid
Compared with 5% fluorouracil, the new 0.5%
formulation, combined with 10% salicylic acid
(Actikerall® [Almirall]) is associated with fewer
side effects. It has been shown to achieve superior
clearance of AK compared with diclofenac gel
(in 74% versus 55% of lesions, respectively), with
complete clearance of all treated AKs (4–10
per patient) in 55% versus 32%, respectively.19
However, it should only be used in small fields,
unlike diclofenac gel. It offers a useful alternative
to cryotherapy for patients with few, or solitary,
hyperkeratotic AKs. The product comes in a
bottle with a brush applicator, so patients
need to be clear about which sites require treat-
ment and must be able to apply the product
at home.
Choosing the correct therapy
In view of the increase in treatment options and
the emphasis on AK usually being viewed as a
field disease, in Table 2 we divide therapy choice
by lesion site and whether the practitioner is seek-
ing to treat only a single or few scattered lesions,
or a small (up to 25 cm2) or large therapy field.
Compliance is likely to be improved when treat-
ments with a short duration of application are
used, but patient preference should drive the final
choice between the options most suitable for a
given presentation �
Declaration of interestColin Morton has advisory board membership with Leo, Meda and Almirall; hehas also received speaker honoraria from Leo, Galderma and Spirit Healthcarewithin the past three years. Megan Mowbray has received speaker honorariafrom Leo. Colin Clark has accepted travel honoraria from Galderma. Girish Guptahas advisory board membership with Leo, Meda and Almirall; he has also re-ceived speaker honoraria from Leo and Meda within the past three years. RobertHerd has advisory board membership with Leo and Meda. Colin Fleming hasgiven consultancy at Almirall and is co-investigator on Leo studies.
The outline for this article was discussed at a clinical guideline review meetingsupported by an educational grant from Leo.
References1. de Berker D, McGregor JM, Hughes BR, British Association of DermatologistsTherapy Guidelines and Audit Subcommittee. Guidelines for the managementof actinic keratosis. Br J Dermatol 2007; 156: 222–230.2. Olsen EA, Abernethy ML, Kulp-Shorten C et al. A double-blind, vehicle-con-trolled study evaluating masoprocol cream in the treatment of actinic keratoseson the head and neck. J Am Acad Dermatol 1991; 24: 738–743.3. Thomson KF, Stables G. Actinic keratosis. Dermatology in practice 2001; 9(4):26–29.4. www.euroderm.org/images/stories/guidelines/guideline_Management_Ac-tinic_Keratoses-update2011.pdf (last accessed 01/08/13)5. Stockfleth E. The paradigm shift in treating actinic keratoses: a comprehensivestrategy. J Drugs Dermatol 2012; 11: 1462–1467.6 Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skincancer and solar keratoses. I. Methods and descriptive results of the South WalesSkin Cancer Study. Br J Cancer 1996; 74: 1302–1307.7 Frost C, Williams G, Green A. High incidence and regression rates of solar ker-atoses in a Queensland community. J Invest Dermatol 2000; 115: 273–277.8. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic ker-atoses and the controversy over treatment: A patient-oriented perspective.ArchDermatol 1991; 127: 1029–1031.9. Stockfleth E, Ulrich C, Meyer T, Christophers E. Epithelial malignancies in organtransplant patients: clinical presentation and new methods of treatment. RecentResults Cancer Res 2002; 160: 251–258.10. www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn.-solar-keratosis (last accessed 01/08/13)11. www.18weeks.scot.nhs.uk/how-to-achieve-and-maintain-18-weeks/patient-pathways/dermatology/ (last accessed 01/08/13)12. http://guidance.nice.org.uk/CSGSTIM/Guidance/Standard2006/pdf/English(last accessed 01/08/13)13. Stockfleth E, Ferrandiz C, Grob JJ et al.Development of a treatment algorithmfor actinic keratoses: a European Consensus. Eur J Dermatol 2008; 18: 651–659.14. Gupta AK, Paquet M, Villanueva E, Britnell W. Interventions for actinic kerato-sis. Cochrane Database Syst Rev 2012; CD004415.15. www.medicines.org.uk/emc/medicine (last accessed 29/10/13)16. www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Infor-mation/human/002204/WC500120044.pdf (last accessed 29/10/13)17. Lebwohl M, Swanson N, Anderson LL et al. Ingenol mebutate gel for actinickeratosis. N Eng J Med 2012; 366: 1010–1019.18. Swanson N, Abramovits W, Berman B et al. Imiquimod 2.5% and 3.75% for thetreatment of actinic keratoses: results of two placebo-controlled studies of dailyapplication to the face and balding scalp for two 2-week cycles. J Am Acad Der-matol 2010; 62: 582–590.19. Stockfleth E, Kerl H, Zwingers T, Willers C. Low-dose 5-fluorouracil in combi-nation with salicylic acid as a new lesion-directed option to treat topically actinickeratoses: histological and clinical study results. Br J Dermatol 2011; 165:1101–1118.
17
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 Therapeutics
www.dermatologyinpractice.co.uk
� Actinic keratosis (AK) is a manifestation of field change in which the surrounding skin is dysplastic.
� Several new treatments are available for AK, offering newoptions to primary care physicians.
� The best choice of treatment depends on the number of lesions, their site, size, the amount of hyperkeratosis and patient preference.
Key points
Table 2. A practical approach to treatment, reflectingcurrent approvals and common practice in the UK
Face/scalp AK Trunk/limb AKLesional • Cryotherapy (curettage for • Cryotherapy (curettage for(1–3 non- thick AK)* thick AK)* clustered) • 0.5% fluorouracil/10% salicylic • 0.5% fluorouracil/10% salicylic acid
acid (Actikerall®) (Actikerall®)†
Small field • 5% fluorouracil (Efudix®) • 5% fluorouracil (Efudix®)(clusters: ~ 4–8 • 0.5% 5-fluorouracil/10% • 0.5% 5-fluorouracil/10% salicylic acid in single area salicylic acid (Actikerall®) (Actikerall®, Almirall)†
< 25 cm2) • Imiquimod 5% (Aldara®) • Imiquimod 5% (Aldara®)†
• Ingenol (Picato®, 0.015%) • Ingenol (Picato® 0.05%)• PDT (Ameluz®/Metvix®)‡ • ALA or MAL-PDT†
Large field • Diclofenac 3% (Solaraze®) • Diclofenac 3% (Solaraze®)(25–200 cm2) • 5% fluorouracil (Efudix®) • 5% fluorouracil (Efudix®)
• Imiquimod 3.75% (zyclara®) • Imiquimod 3.75% (zyclara®)†
• PDT‡ • PDT†
* By experienced practitioners.† Topical therapy without specific licence for this indication. ‡ Usually initiated in specialistdermatology department. ALA = aminolevulinic acid; AK = actinic keratosis; MAL-PDT = methyl aminolevulinatephotodynamic therapy; PDT = photodynamic therapy
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Barry MonkMA FRCP ConsultantDermatologist,Bedford Hospital
IMAG
ES/S
UPER
STOC
K
18
recent development of a systemic agent,
vismodegib, used for difficult basal cell
carcinomas, means that pharmaceutical
companies are applying their brains and
money to this challenging area.
In medicine, as in life, one never knows
what will happen next, but it could well be
that, in ten years, a dermatological surgeon
will be as obsolete as a scrivener or a cursitor
(who would deliver messages for lawyers, like
a 19th century version of email). I can only
suggest that dermatology trainees of today
don’t get too focused on one small part of
our wonderful subject �
Declaration of interestNone declared
www.dermatologyinpractice.co.uk
Occupational health
Monk’s moments DERMATOLGY IN PRACTICE 2013; Vol 19 No 4
� Neurosurgeonshave had to cope with a dramaticdecline in work. Will dermatologicalsurgeons findthemselves in thesame position?
In times gone by, it was often possible to tell
what a patient’s job was by the occupational
marks on their skin – the coal dust tattooed
into the skin (colliers’ stripes) of the miner or
the presternal bursa of the bootmaker, for
example. Many traditional industries have
vanished and are now remembered by
surnames such as Fuller, Fletcher, Wainwright
and Salter. Towns and cities also used to be
identifiable by their traditional trades but are
now recalled by the old nicknames of their
football teams: The Cobblers (Northampton
Town) and The Hatters (Luton Town);
incidentally, the term ‘mad as a hatter’ derives
from chronic mercury poisoning, which was a
notorious hazard of preparing felt for use in
hat-making.
Medicine, of course, is not immune to changes
in working practices. The traditional general
surgeon, capable of turning his hand to anything,
or the general physician, able to take a holistic
overview of the undiagnosed case, are now but
nostalgic memories. Cardiac surgery has all but
vanished, thanks to the remarkable skills of
interventional cardiologists and to the general
decline in coronary artery disease. Ear, nose and
throat surgeons now twiddle their thumbs
looking for work, having lost their stock in trade
of tonsils, adenoids and grommets. Neurosurgery
has had to cope with a dramatic decline in head
injury resulting from crash helmets, better car
design and safety at work. It is not of course a
one-way process; infectious disease medicine,
which had all but vanished by the 1970s,
suddenly underwent an enormous resurgence
with the appearance of AIDS just a few years later.
So what about dermatology? Surely there will
always be enough work to keep us busy,
especially given the broad spectrum that we
cover. When talking to trainees, a surprising
number of them want to become dermatological
surgeons, sometimes to the complete exclusion
of general dermatology. Faced with the present
avalanche of skin cancers, there would certainly
seem to be plenty for them to do, but how long
will this work come pouring in? We now
recognise that non-melanoma skin cancer results
from a ‘field change’ and it is therefore much
more logical to treat cancers and pre-cancers with
non-surgical therapies, which can treat the entire
‘at risk’ area. Our presently available agents –
photodynamic therapy, imiquimod and others –
are clearly not the complete answer. But the
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
Richard JerromBMedSci(Hons) BMBSFy1 MedicineNeill HepburnMD FRCP ConsultantDermatologist,Lincoln CountyHospital
First described by pathologist Alexander Bres-
low in 1970, ‘Breslow thickness’ is a measure-
ment of the depth of invasion of melanoma
into the skin tissue, and remains the most reli-
able indicator of disease prognosis.
The Breslow thickness is defined as the maxi-
mum vertical depth, in millimetres, of melanoma
cancer cell infiltration below the granular cell
layer, which is the most superficial layer of living
skin cells in the epidermis (see Figure 1). It is meas-
ured from excisional biopsies in the laboratory
using an ocular micrometer. This measurement
must include any smaller satellites of cancer cells
that may be deeper than the main tumour mass.
When a diagnosis of melanoma is made, the
Breslow thickness is routinely included in the
pathology report, due to its significant correlation
with disease outcome. A Breslow thickness greater
than 1.5 mm is generally considered to be high-risk
with a significantly poorer prognosis (see Table 1).
Other important prognostic indicators in
melanoma skin cancer are the presence of ulcera-
tion; lymph node involvement; and evidence of
metastatic disease. These features are used to-
gether to stage the disease.
In addition to being used directly as a prognos-
tic indicator, the Breslow thickness of a melanoma
also determines the re-excision margins �
Declaration of interestThe authors declare that there is no conflict of interest.
Further reading1. Marsden JR, Newton-Bishop JA, Burrows L et al. Revised U.K. guidelines for themanagement of cutaneous melanoma 2010. Brit J Dermatol 2010; 163: 238–256.2. Mackie RM, Bray CA, Hole DJ et al. Incidence and survival from malignantmelanoma in Scotland: an epidemiological study. Lancet 2002; 360: 587–591.3. Melanoma Research Foundation. Staging Melanoma, 2011. www.melanoma.org/learn-more/melanoma-101/staging-melanoma (last accessed 22/05/13)4. Graham-Brown R, Burns T. Lecture Notes Dermatology. Oxford: Blackwell Pub-lishing, 2007.
19
DERMATOLOGY IN PRACTICE 2013; Vol 19 No 4 FAQs
www.dermatologyinpractice.co.uk
What is ‘Breslowthickness’ in melanoma?
Table 1. Approximate re-excision margins and five-year survival
Breslow Surgical 5-year thickness re-excision survival (mm) margin (cm) (%)<1.0 1 95–100
1.01–2.0 1–2 80–96
2.01–4.0 2–3 60–75
>4.0 >3 37–50
Breslow thickness = depth (mm) from (a) to (b)
Epidermis
Dermis
Hypodermis
Stratum corneum
Stratum lucidum
Stratum spinosum
Stratum basale
Reticular dermis
(b) Deepest invasive malignant melanoma cells
Adipose tissue
Papillary dermis
(a) Stratum granulosum (granular cell layer)
� Figure 1.How to measureBreslow thickness
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]
� AccessDermatology in practice online today
The latest issue of Dermatology in practice is
available in three file formats: PDF, EPUB (for your
tablet or smartphone) and MOBI (for your Kindle).
Access is free for healthcare professionals.
To receive notification when a new issue is
published, register for our e-alert service at
www.dermatologyinpractice.co.uk
Archive contentAccess to the archive requires a subscription.
You can browse back issues or search by
keyword to research a particular topic.
And if you’d like a print copy of a
back issue of the journal, visit our webstore:
http://webstore.haywardpublishing.co.uk
HaywardMedical Communications www. h a yw a r d . c o . u k
What can we do for you?
Go to
www.dermatologyinpractice.co.uk
now to view the latest issue free of charge!
������������� ������ �����������
����������� �����������������������������
������������������ ������������� ����������� ����������������������
�����������������!����������������
������������ ����������������
� � �������� ������ �����������������������������������������
��������� ����
������������������ ��� ����������
��� ��������� ���������� �����
��������������������������� ���!����������������������������������������������������������
��������� ��� �������������
����������������� ��� �
����������������������������������������
����������in practice
���������� ���������������� �����������!����������������
�������������� ����� ������������!��������������"���������
print | online | e-reader
Copyright © Hayward Medical Communications 2013. All rights reserved. No unauthorised reproduction or distribution. For reprints or permissions, contact [email protected]